Studies on the molecular properties of alpha-synuclein and the mechanisms of alpha-synuclein-related pathology bear important implications for our understanding of the neurodegenerative process that underlies PD. In particular, molecular interactions and toxic mechanisms that promote the tendency of alpha-synuclein to aggregate could also play a role in the development of the typical intraneuronal inclusions (i. e., Lewy bodies) seen in PD brain. Furthermore, elucidating the relationship between alpha-synuclein aggregation and neuronal injury could help to explain the role of Lewy bodies in nigrostriatal degeneration in PD. This integrative Research Project is intended to bridge two parent grants, both of which investigate the pathophysiology of alpha-synuclein. Results of studies in progress indicate that interactions between alpha-synuclein and neurotoxicants can induce protein aggregation and possibly contribute to neurodegeneration. The new proposed experiments are designed to provide a mechanistic basis for these pathological events. They will assess the role of oxidative stress as a key factor for the development of alpha-synuclein-containing inclusions and alpha-synuclein-induced neuronal injury, and determine whether the presence of dopamine within nigrostriatal neurons renders these cells particularly vulnerable to oxidative stress-mediated alpha-synuclein pathology.